Benzothiadiazine derivatives



United States Patent 3,057,863 BENZOTHIADIAZINE DERIVATIVES Harry LouisYale, New Brunswick, N.J., assignor to Olin Mathieson ChemicalCorporation, New York, N.Y., a corporation of Virginia No Drawing.Original application Mar. 25, 1959, Ser. No. 801,691. Divided and thisapplication Feb. 10, 1961, Ser. No. 88,291

3 Claims. (Cl. 260-243) This application is a division of myapplication, Serial No. 801,691, filed March 25, 1959.

This invention relates to new benzothiadiazine derivatives, and moreparticularly to new trifiuorornethylbenzothiadiazine-sulfonamidederivatives, one tautomer of which has the general formula S O r il-(lower alkyl) YNHSO:

NHBSOP SOzNHa with either the acyl halide (preferably chloride) or acidanhydride of a lower alkanoic acid to yield new intermediates of thegeneral formula YNHSOr 0 FT T NBC 0 (lower alkyl) wherein the Ys are thesame or dilferent and represent either hydrogen or the acyl radical ofthe acid reagent. The nature of the intermediate depends on theproportion of acid to sulfonamide. When a large excess of acid ispresent a triacylated product (both Ys are lower alkanoyl) is formed.If, however, four or less molar equivalents of acid (or two or lessmolar equivalents of anhydride) are used, then a mixture of the mono-(both Ys are hydrogen) and di- (one Y is lower alkanoyl and the other ishydrogen) acylated derivatives are formed. In both instances, however,the reaction is preferably conducted at an elevated temperature belowabout 150 Upon pyrolysis the intermediates cyclize to yield the finalproducts of this invention. This pyrolysis is accomplished by heatingthe intermediate to a temperature above about 200 C. The nature of thefinal product will depend upon the degree of acylation of theintermediate. Thus, a triacylated intermediate will yield a productwherein Y is lower alkanoyl, whereas the monoand diacylatedintermediates both yield a product wherein Y is hydrogen.

The sulfonamide reactants can be prepared as disclosed in theapplication of Yale et al., Serial No. 698,377, filed November 25, 1957,and specifically include S-amino- Patented Oct. 9, 1962 a,a,oz trifluoro2,4 toluenedisulfonamide, 4aminoa,a,a-trifiuoro-3,S-toluenedisulfonamide, and Z-aminO-a,a,u-trifluOride-B,5-toluenedisulfonamide. Among the suitable acidreactants may be mentioned the acyl halides and 5 particularly the acidanhydrides of the lower alkanoic acids of at least two carbon atoms(e.g. acetic anhydride,

propionic anhydride, butyric anhydride, valeric anhydride, and enanthicanhydride).

The free benzothiadiazine products, thus formed, can then, if desired betreated with alcoholic alkali metal hydrocides (e.g. potassiumhydroxide), whereby the alkali metal salts are formed.

The following examples illustrate the invention (all temperatures beingin centigrade):

EXAMPLE 1 3-Methyl-6-Triflu0r0methyl-1,2,4-Benz0thiadiazine-7-Sulf0namide 1,1 -Di0xide (a) Preparation ofS-acetamido-ogu,u-trifluoro-ZA-toluenesulfonamide and5-acetamido-a,a,a.-triflu0r0-4-acetamidosulfonyl-Z-toluenesulf0namide.Amixture of 9.6 g. (0.03 mole) of5-amino-a,a,a-trifluoro-2,4-toluenedisulfonamide, 6.12 g. (0.06 mole) ofacetic anhydride and 50 ml. of glacial acetic acid is refluxed for threehours and then concentrated in vacuo from the steam bath. The residue isa brown glass which when warmed with 50 ml. of water solidifies. Thesolid is filtered and recrystallized from Water to give a product havingan M.P. of about 2l5-2l8 which represents a mixture of the monoacetyland di-acetyl derivatives.

(b) Preparation :of 3-methyl-o-trifluoromethyl-l,2,4-benzothiadiazine-7-sulfonamide 1,1-di0xide.-The mixture obtained in step(a) is pyrolized by placing in an oil bath preheated to 200 and thenallowing the temperature to rise to 250 during two hours. The resultantsolid, upon recrystallization from water gives about 3 g. of 3- methyl 6trifluoromethyl 1,2,4 benzothiadiazine 7- sulfonamide 1,1-dioxide, M.P.about 338-340.

EXAMPLE 2 Dipotassium Salt of 3-Methyl6-Trifluorom ethyl-1,2,4-Benzothiadiazine-7-Sulf0namide 1,1-Dioxide To a solution of 6.5 g. of85% potassium hydroxide in 100 ml. of ethanol is added gradually withshaking 17.2 g. of 3-methyl-6-trifluoromethyl-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. The solid dissolves. The re sulting alcoholicsolution is concentrated in vacuo to yield the dipotassium salt of3-methyl-6-trifluoromethyl-1,2,4- benzothiadiazine-7-sulfonarnide1,1-dioxide.

Similarly, using an equivalent quantity of sodium hydroxide instead ofpotassium hydroxide in the procedure of Example 2, the disodium salt isobtained. Furthermore, if only 3.25 g. of 85% potassium hydroxide isused in Example 2, the monopotassium salt is obtained.

EXAMPLE 3 3-Methyl-7-Trifluoromethyl-1,2,4-Benz0thiadiazine-5- Sulfonamide 1,1-Dz'0xide Following the procedure of Example 1, butsubstituting 9.6 g. of 4-amino-a,u,a-trifiuoro-3,5-toluenedisulfonamidefor the 5-amino-a,a,a-trifluoro-2,4-toluenedisulfonamide,

a mixture of the mono and diacetyl derivatives are first 65 formed, fromwhich 3-methyl-7-trifluoromethyl-1,2,4-

benzothiadiazine-S-sulfonamide 1,1-dioxide is obtained.

EXAMPLE 4 3-Methyl-5-Triflu0r0methyl-1,2,4-Benz0thiadiazine-7-Sulfonamide 1,1-Dioxide Following the procedure of Example 1, butsubstituting 9.6 g. of 2-amino-a,a,a-trifluoro-3,S-toluenedisulfonamidefor the 5-amino-a,u,u-trifiuoro-2,4-toluenedisulfonamide, a mixture ofthe mono and diacetyl derivatives are first obtained from which3-rnethyl-S-trifiuoromethyl-1,2,4- benzothiadiazine-7-sulfonamide1,1'dioxide is prepared.

EXAMPLE 5 3-Ethyl-6-Triflu0r0methyl-1,2,4-Benz0thiadiazine-7-Sulfonamide 1,1-Dixia'e Following the procedure of Example 1, butsubstituting 7.8 g. (0.06 mole) of propionic anhydride for the aceticanhydride and 50 ml. of propionic acid the acetic acid in step (a),there is first obtained a mixture ofS-propionamido-a,a,a-trifiuoro-2,4-to1uenedisulfonamide and-propionamido a,u,a trifiuoro 4 propionamidosulfonyl-2-toluenesulfonarnide, and then by the procedure of step (b), 3-ethyl 6trifiuoromethyl-l,2,4-benzothiadiaZine-7- sulfonarnide 1,1-dioxide.

Similarly, valeric anhydride and enanthic anhydride, substituted inequivalent amount, yield first a mixture of the 5-mono and 4,5-diacylated derivatives, and then 3-nbutyl 6trifiuoromethyl-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide and3-n-hexyl-6-trifluoromethyl-1,2,4- benzothiadiazine-7-sulfonamide1,1-dioxide, respectively.

EXAMPLE 6 7-11 cezylsulfamyl-3-Methyl-6-Trifluor0methyl-1 ,2,4-Benzothiadiazine 1,1-Di0xide (a) Preparation of5-acetamido-u,a,a-triflu0r0-2,4-diacetamidosulfonyltoluene.A mixture of25 g. (0.078) of 5-amino-a,u,a-trifluoro-2,4-toluenedisulfonamide and100 g. (0.91 mole) of acetic anhydride is heated under reflux for twohours, cooled, and the crystalline solid filtered on a sintered glassfunnel. Recrystallization from aqueous acetonitrile (2:1) givesS-acetamido-u,a,u-trifluoro-2,4- diacetamidosulfonyltoluene, M.P. aboutZOO-202.

(b) Preparation of7-acetylsulfamyl-3-methyl-6-trifluoromethyl-1,2,4-benz0thiadiazinel,1-di0xide.15 g. of5-acetamido-a,a,a-trifiuoro-2,4-diacetamidosulfonyltoluen is pyrolyzedfor two hours in an oil bath at 215-225 The pyrolysis product isdissolved in 500 ml. of boiling acetone, the solution is decolorizedwith activated charcoal, filtered and the filtrate concentrated todryness. The residual white solid is recrystallized from aqueousisopropanol (1:1) to give about 4.5 g. of 7-acetylsulfamyl-3-methyl-6-trifiuoromethyl-1,2,4-benzothiadiazine 1,1-dioxide, M.P.about 285287.

4 EXAMPLE 7 3-Erhyl-6-Trifluoromethyl-1,2,4-Benz0thiadiazine-7-Sulfonamide 1,1-Dioxide (a) Preparation of5-propionamid0-u,u,a-triflu0r0-2,4- dipropionamidosulfonyltoluene.Amixture of 25 g. (0.08 mole) ofS-arnino-a,a,u-trifluoro-2,4-toluenedisulfonamide and 104 g. (0.8 mole)of propionic anhydride is heated under reflux for two hours and thenconcentrated to dryness. The crude product is recrystallized fromaqueous acetonitrile (9:1) to give an analytical sample of 5propionamido-a,a,a-trifiuoro-2,4-dipropionamidosulfonyltoluene, M.P.about 227229.

(b) Preparation of 3-efhyl-6-triflu0r0methyl-1,2,4-benzothiadiazine-7-sulf0namide 1,1-di0xide.31 g. of 5-propionamido-a,a,wtrifiuore-2,4-dipropionamidosulfonyltoluene isdissolved in 310 ml. of Dowthertn A preheated to 210. The solution iskept two hours at 210-215", cooled, and the crystalline solid filtered.The solid is washed with ethyl ether and recrystallized from aqueousisopropanol (1: 1) to give about 10 g. of3-ethyl-6-trifluoromethyl-1,2,4benzothiadiazine-7-sulfonamide1,1-di0xide, M.P. about 345-347 (dec.).

The invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. A compound selected from the group consisting of benzothiadiazines ofthe formula /S g: YNHS o1 F: C-(lower alkyl) and alkali metal saltsthereof, wherein Y is lower alkanoyl. 2. 3-(loweralkyl)-6-trifiuoromethyl-7-(lower alkanoyl)sulfamyl-l,2,4-benzothiadiazine 1,1-dioxide.

3. 3 methyl 6-trifiuoromethyl-7-acetyl-sulfamyl-1,2,4- benzothiadiazine1,1-dioxide.

References Cited in the file of this patent UNITED STATES PATENTS 52,809,194 Novello Oct. 8, 1957 2,894,948 De Stevens et a1 July 14, 19592,910,476 Novello Oct. 27, 1959

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BENZOTHIADIAZINES OFTHE FORMULA